Synthesis, spectroscopic characterizations and quantum chemical computational studies of (Z)-4-[(E)-(4-fluorophenyl)diazenyl]-6-[(3-hydroxypropylamino)methylene]-2-methoxycyclohexa-2,4-dienone

In this study, the molecular structure and spectroscopic properties of the title compound were characterized by X-ray diffraction, FT-IR and UV-vis spectroscopies. These properties were also investigated using DFT method. The most convenient conformation of title compound was firstly determined. The geometry optimizations in gas phase and solvent media were performed by DFT methods with B3LYP adding 6-31G(d) basis set. The differences between crystal and computational structures are due to crystal packing in which hydrogen bonds play an important role. UV-vis spectra were recorded in different organic solvents. The results show that title compound exists in both keto and enol forms in DMSO, EtOH but it tends to shift towards enol form in benzene. The polar solvents facilitate the proton transfer by decreasing the activation energy needed for Transition State. The formation of both keto and enol forms in DMSO and EtOH is due to decrease in the activation energy. TD-DFT calculations starting from optimized geometry were carried out in both gas and solution phases to calculate excitation energies of the title compound. The non-linear optical properties were computed at the theory level and the title compound showed a good second order non-linear optical property. In addition, thermodynamic properties were obtained in the range of 100-500K.     

Synthesis,spectroscopic and crystal structure analysis of 2-(4-fluorobenzyl)-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole and its morpholinomethyl derivative

The preparation of 2-(4-fluorobenzyl)-6-(4-methoxyphenyl)-5-morpholin-1-ylmethyl imidazo[2,1-b][1,3,4]thiadiazole via the intermediate 2-(4-fluorobenzyl)-6-(4-methoxyphenyl)Imidazo[2,1-b][1,3,4] thiadiazole is described. Elemental analysis, IR spectrum, ¹H NMR and X-ray crystal structure analyses were carried out to determine the compositions and molecular structures of the two compounds. The crystal packing exhibits intermolecular C–H?O, C–H?N, C–H?F and π–π stacking interactions leading to the formation of the supramolecular network.     

Two polymorphic forms of N‐(4‐chloro­phenyl)‐5‐[(4‐chlorophenyl)aminomethyl]‐6‐methyl‐2‐phenyl­pyrimidin‐4‐amine

Two polymorphic forms of the title compound, C₂₄H₂₀Cl₂N₄, were obtained and characterized using X‐ray crystal structure analysis. Colourless crystals of polymorph (Ia) were obtained from the oily mother residue. Recrystallization of polymorph (Ia) from an acetone–methanol mixture resulted in pale‐yellow crystals of polymorph (Ib). The major feature distinguishing the two polymorphic forms is their inter­action modes, and hence their packing arrangements. In the crystal structure of polymorph (Ia), there are N—H⋯N hydrogen bonds and also aromatic π–π stacking inter­actions between mol­ecules. The mol­ecules of polymorph (Ib) are linked by N—H⋯Cl hydrogen bonds only.     

A third polymorph of 4‐(2,6‐difluorophenyl)‐1,2,3,5‐dithiadiazolyl

The crystal structure of a third polymorphic form of the known 4‐(2,6‐difluorophenyl)‐1,2,3,5‐dithiadiazolyl radical, C₇H₃F₂N₂S₂, is reported. This new polymorph represents a unique crystal‐packing motif never before observed for 1,2,3,5‐dithiadiazolyl (DTDA) radicals. In the two known polymorphic forms of the title compound, all of the molecules form cis‐cofacial dimers, such that two molecules are π‐stacked with like atoms one on top of the other, a common arrangement for DTDA species. By contrast, the third polymorph, reported herein, contains two crystallographically unique molecules organized such that only 50% are dimerized, while the other 50% remain monomeric radicals. The dimerized molecules are arranged in the trans‐antarafacial mode. This less common dimer motif for DTDA species is characterized by π–π interactions between the S atoms [S...S = 3.208 (1) Å at 110 K], such that the two molecules of the dimer are related by a centre of inversion. The most remarkable aspect of this third polymorph is that the DTDA dimers are co‐packed with monomers. The monomeric radicals are arranged in one‐dimensional chains directed by close lateral intermolecular contacts between the two S atoms of one DTDA heterocycle and an N atom of a neighbouring coplanar DTDA heterocycle [S...N = 2.857 (2) and 3.147 (2) Å at 110 K].     

Characterization of polymorphs of a novel quinolinone derivative, TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone)

The polymorphic forms and amorphous form of TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone), a newly developed antiallergenic compound, were characterized by powder X-ray diffractometry, thermal analysis, infrared spectroscopy and solid state 13C-NMR. The intrinsic dissolution rates of polymorphic forms were measured using the rotating disk method at 37 degrees C. The dissolution rates correlated well with the thermodynamic stability of each polymorphic form. These dissolution properties were clearly reflected in the oral bioavailability of TA-270 in rats. The transition behavior for each polymorph and for the amorphous form was studied under the high temperature and humidity conditions. The beta- and delta-forms were transformed into the alpha-form by heating. The amorphous form was also easily crystallized into alpha-form by heating, however it was relatively stable under humidified conditions. The internal molecular packing of each polymorph was estimated from IR and solid state NMR spectral analysis.     

Preparation and characterization of finely dispersed drugs. 5. Ethyl 3,5-di(acetylamino)-2,4,6-triiodobenzoate

Controlled precipitation of the diagnostic imaging agent ethyl 3,5-di(acetylamino)-2,4,6-triiodobenzoate has been used to produce fine particles of various sizes, morphologies, and degrees of crystallinity, which depended on experimental conditions. In addition, two distinct polymorphic forms of the drug have been fully characterized by single crystal X-ray diffraction studies, and evidence for a third polymorph was also observed. Some of the so prepared dry particles were coated with a thin layer of silica.     

Conformational polymorphs of 3‐cyclopropyl‐5‐(3‐methyl‐[1,2,4]triazolo[4,3‐a]pyridin‐7‐yl)‐1,2,4‐oxadiazole

The dipharmacophore compound 3‐cyclopropyl‐5‐(3‐methyl‐[1,2,4]triazolo[4,3‐a]pyridin‐7‐yl)‐1,2,4‐oxadiazole, C₁₂H₁₁N₅O, was studied on the assumption of its potential biological activity. Two polymorphic forms differ in both their molecular and crystal structures. The monoclinic polymorphic form was crystallized from more volatile solvents and contains a conformer with a higher relative energy. The basic molecule forms an abundance of interactions with relatively close energies. The orthorhombic polymorph was crystallized very slowly from isoamyl alcohol and contains a conformer with a much lower energy. The basic molecule forms two strong interactions and a large number of weak interactions. Stacking interactions of the `head‐to‐head' type in the monoclinic structure and of the `head‐to‐tail' type in the orthorhombic structure proved to be the strongest and form stacked columns in the two polymorphs. The main structural motif of the monoclinic structure is a double column where two stacked columns interact through weak C—H…N hydrogen bonds and dispersive interactions. In the orthorhombic structure, a single stacked column is the main structural motif. Periodic calculations confirmed that the orthorhombic structure obtained by slow evaporation has a lower lattice energy (0.97 kcal mol^?1) compared to the monoclinic structure.     

Anion-/cation-directed reaction routes to polymorphic forms of a pyrazole-type ligand and its coordination compounds with zinc. Key structural differences between polymorphs’

Synthetic paths toward the two polymorphs of a monohydrate, one anhydrous polymorph of 1-carboxamidino-5-hydroxy-3-methylpyrazole (hcmp) and two polymorphs of zinc complexes containing hcmp ligand are presented. By choosing ions which are not part of the final product, it is possible to direct the synthesis toward the particular polymorph. In all three modifications of hcmp, the same hydrogen bonding motif appears, leading to formation of similar molecular chains. Differences arise due to different modes of chain aggregation and the presence of solvent water. Analysis of the crystal packing and the energetic features of hcmp polymorphs is made using the PIXEL model. The thermal decomposition processes are examined using differential scanning calorimetry and thermogravimetry. Analysis of crystal packing in the two polymorphs of zinc complex suggests the key role of the hydrogen bonding capacity of the aqua ligand for the appearance of the two polymorphic forms. In both polymorphs of zinc complex, stacking interactions have an important role. However, the enhanced hydrogen bonding capacity of the aqua ligand influences the formation of multistacking arrangement.     

Polymorphism in Fe[(p-IC6H4)B(3-Mepz)3]2 (pz = pyrazolyl): impact of supramolecular structure on an iron(II) electronic spin-state crossover

The new ligands Na[(p-IC6H4)B(3-Rpz)3] (R = H, Me) have been prepared by converting I2C6H4 to IC6H4SiMe3 with Li(t)Bu and SiMe3Cl, and then to IC6H4BBr2 with BBr3 and subsequent reaction with 3 equiv of (un)substituted pyrazole and 1 equiv of NaO(t)Bu. These new ligands react with FeBr2 to give either purple, low-spin Fe[(p-IC6H4)B(pz)3]2 or colorless, high-spin Fe[(p-IC6H4)B(3-Mepz)3]2. Depending upon the crystallization conditions, Fe[(p-IC6H4)B(3-Mepz)3]2 can exist both as two polymorphs and as a methylene chloride solvate. An examination of these polymorphs by variable-temperature X-ray crystallography, magnetic susceptibility, and Mossbauer spectroscopy has revealed different electronic spin-state crossover properties for each polymorph and yields insight into the influence of crystal packing, independent of other electronic perturbations, on the spin-state crossover. The first polymorph of Fe[(p-IC6H4)B(3-Mepz)3]2 has a highly organized three-dimensional supramolecular structure and does not undergo a spin-state crossover upon cooling to 4 K. The second polymorph of Fe[(p-IC6H4)B(3-Mepz)3]2 has a stacked two-dimensional supramolecular structure, a structure that is clearly less well organized than that of the first polymorph, and undergoes an abrupt iron(II) spin-state crossover from high spin to low spin upon cooling below ca. 130 K. The crystal structure of the methylene chloride solvate of Fe[(p-IC6H4)B(3-Mepz)3]2 has a similar stacked two-dimensional supramolecular structure, but the crystals readily lose the solvate. The resulting desolvate undergoes a gradual spin-state crossover to the low-spin state upon cooling below ca. 235 K. It is clear from a comparison of the structures that the long-range solid-state organization of the molecules, which is controlled by noncovalent supramolecular interactions, has a strong impact upon the spin-state crossover, with the more highly organized structures having lower spin-crossover temperatures and more abrupt spin-crossover behavior.     

A new conformer of 1,4,7‐tris(p‐tolylsulfonyl)‐1,4,7‐triazacyclononane

A second polymorphic form (form II) of the previously reported 1,4,7‐tris(p‐tolylsulfonyl)‐1,4,7‐triazacyclononane (form I), C₂₇H₃₃N₃O₆S₃, is presented. The molecular structures of the two forms display very different conformations, thus prompting the two forms to crystallize in two different space groups and exhibit quite diverse crystal structure assemblies. Form I crystallizes in the triclinic space group P, while form II crystallizes in the monoclinic space group P2₁/n. The main differences between the two molecular structures are the conformations of the p‐tosyl groups relative to each other and to the macrocyclic ring. The resulting crystal packing displays no classical hydrogen bonds, but different supramolecular synthons give rise to different packing motifs.     

The outlined polymorph selection of iPB-1 revealing by incorporation of a dentritic polymer

By incorporating a hydrophilic dentritic polyester into polymorphic isotactic polybutene-1 (iPB-1), we successfully decreased its viscosity as designed to trigger the melt crystallisation of form III due to the proposed decrease of the interactions between the iPB-1 chain sequences. In addition to the usual form II formation, the form III formation resulting from cooling the iPB-1 melt at suitable cooling rates has been verified by the DSC, WAXD, and in-situ synchrotron WAXS measurements. It was proposed that the form III melt crystallisation occurs after the 4/1 helix conformation formation in the iPB-1 melt and the following alignment of the resulting 4/1 helices. Once the interactions between the iPB-1 chain sequences are sufficiently strong as in the usual iPB-1 melt, the collapse of the 4/1 into the 11/3 helix conformation would occur and finally trigger the generally observed melt crystallisation of form II. Thus, we first outlined the polymorph selection process of iPB-1 based on the helix conformation formation and the following alignment of the helices which finally result in crystallisation of iPB-1 into corresponding crystal forms. The results are helpful for understanding of both the polymorph selection of polymorphic polymers like iPB-1 and the general polymer crystallisation.     

Crystal Structure and Spectral Characters of 2-（4-Methylbenzoly）-3-（4-chlrolphenyl） -4-（1,2,4-triazole）-5-anilino-thiopene

1 INTRODUCTION The triazole derivatives were widely studied because they represent the largest group of modern fungicides and extensively used in both human and veterinary therapy and in agriculture[1～3]. For exam- ple, there are commercially available …     

Crystal structure of poly(ethylene-oxide) supramolecular assemblies

The formation of poly(ethylene oxide) (PEO) supramolecular complexes is discussed in terms of intermolecular interactions and molecular packing. On the basis of the different known crystal structures, several mechanisms are proposed. First, the PEO complexes can be formed by an Intercalation or Inclusion process, guest molecules diffusing into the PEO unit cell. On the other hand, molecular complexes based on hydrogen bonding cannot be obtained by such a way, their formation requires the complete removal of the initial PEO structure either by melting or dissolution. Finally the relations between the crystal lamellar morphology, the host-guest interactions and the PEO chain mobility are discussed.     

Crystals at a Carrefour on the Way through the Phase Space: A Middle Path

Multiple supramolecular functionalities of cyclic α-alkoxy tellurium-trihalides (including Te---O, Te---X (X = Br, I) and Te---π(C=C) supramolecular synthons) afford rich crystal packing possibilities, which consequently results in polymorphism or Z’ > 1 crystal structures. Example of three crystal forms of cyclohexyl-ethoxy-tellurium-trihalides, one of which combines the packing of two others, affords a unique model to observe the supramolecular synthon evolution at the early stages of crystallization, when crystals on the way find themself at a carrefour between the evolutionally close routes, but fail to choose between two energetically close packing patterns, so taking the “middle path”, which incorporates both of them (and results in two crystallographically independent molecules). In general, this allows a better understanding of the existing structures, and an instrument to search for the new polymorphic forms.     

Polymorphic forms of lupane triterpenoid betulonic aldehyde (betulonal)

The lupane triterpenoid betulonic aldehyde [also known as betulonal; systematic name: lup‐20(29)‐en‐28‐al‐3‐one, C₃₀H₄₆O₂] is a product of betulin oxidation. Crystals were obtained from hexane [form (I)] and dimethyl sulfoxide [form (II)] solutions. Forms (I) and (II) are both orthorhombic. The molecular geometric parameters in the two forms are similar, but the structures are different with respect to the crystal packing. Polymorph (I) contains two independent molecules in the asymmetric unit, while polymorph (II) contains only one molecule, which has a disordered aldehyde group [the disorder ratio is 0.769 (4):0.231 (4)]. In each molecule, the six‐membered rings have chair conformations, whereas the cyclopentane ring in each molecule adopts an envelope conformation. All the rings in the lupane nucleus are trans‐fused. The extended structures of both polymorphs are stabilized by weak intermolecular C—H...O and van der Waals interactions. Weak intramolecular C—H...O interactions are also observed.     

QTAIM application in drug development: prediction of relative stability of drug polymorphs from experimental crystal structures

Prediction of the most stable crystal form based on the strongest intermolecular hydrogen bonds (HBs) only, was successfully applied to ten polymorphic drug systems, using the Quantum Theory of Atoms in Molecules (QTAIM). The results of the predictions were demonstrated to be superior to the thermodynamic stability ranking based on molecular mechanical (COMPASS forcefield), DFT and DFT-D calculations, as well as on the QTAIM predictions based on the total intermolecular HBing interactions strength. The obtained results support the validity of the best donor/best acceptor hierarchical approach for polymorph stability analysis of drug-like molecules: weak interactions are not as important for stability ranking as the strongest HBs. In addition, the proposed QTAIM approach allowed a reasonable ranking of the relative stability of multiple polymorphic crystalline forms of two test systems, axitinib and sulfathiazole.     

Polymorphs and Polymorphic Cocrystals of Temozolomide

Crystal polymorphism in the antitumor drug temozolomide (TMZ), cocrystals of TMZ with 4,4′‐bipyridine‐N,N′‐dioxide (BPNO), and solid‐state stability were studied. Apart from a known X‐ray crystal structure of TMZ (form 1), two new crystalline modifications, forms 2 and 3, were obtained during attempted cocrystallization with carbamazepine and 3‐hydroxypyridine‐N‐oxide. Conformers A and B of the drug molecule are stabilized by intramolecular amide N? H???N_imidazole and N? H???N_tetrazine interactions. The stable conformer A is present in forms 1 and 2, whereas both conformers crystallized in form 3. Preparation of polymorphic cocrystals I and II (TMZ?BPNO 1:0.5 and 2:1) were optimized by using solution crystallization and grinding methods. The metastable nature of polymorph 2 and cocrystal II is ascribed to unused hydrogen‐bond donors/acceptors in the crystal structure. The intramolecularly bonded amide N–H donor in the less stable structure makes additional intermolecular bonds with the tetrazine C?O group and the imidazole N atom in stable polymorph 1 and cocrystal I, respectively. All available hydrogen‐bond donors and acceptors are used to make intermolecular hydrogen bonds in the stable crystalline form. Synthon polymorphism and crystal stability are discussed in terms of hydrogen‐bond reorganization.     

A new polymorphic form of bis(acetato‐κO)bis[2‐(pyridin‐2‐yl)ethanol‐κ2N,O]nickel(II)

A new polymorph of a mononuclear nickel(II) acetate complex with 2‐(pyridin‐2‐yl)ethanol ligands, [Ni(CH₃COO)₂(C₇H₉NO)₂], has been prepared and structurally characterized. Its molecular structure resembles the structures of two previously reported polymorphs in that the Ni^II atom is located on an inversion centre and is coordinated by pairs of acetate and 2‐(pyridin‐2‐yl)ethanol ligands. The acetate anions are coordinated in a monodentate manner, while the 2‐(pyridin‐2‐yl)ethanol ligands are coordinated in a bidentate chelating mode involving the endocyclic N atom and the hydroxy O atom of the ligand side chain. A strong bifurcated intramolecular hydrogen‐bond interaction was observed involving the hydroxy O atom as donor and both acetate O atoms as acceptors. No classical intermolecular hydrogen‐bond contacts were observed. However, the crystal packing is effected through π–π and C—H...π interactions, giving rise to a different packing arrangement. A brief comparison of the three polymorphic forms is presented.     

Crystalline polymorphism and molecular structure of sodium pravastatin

In this work different crystallization processes of sodium pravastatin are explored and a new polymorph is obtained. The analytical results of powder X-ray diffraction (PXRD) and thermal analysis for this new polymorph indicate that it is different from the polymorphs previously reported. This new crystal form shows different physical-chemical properties than the previous forms, such as crystallographic structure, thermal behavior, and melting point, 181.5 degrees C. Besides, all crystallization processes previously reported use an aprotic solvent as antisolvent. However, we propose a new crystallization process for sodium pravastatin that uses only protic solvents, overcoming industrial scaling and environmental problems. Variable-temperature PXRD experiments show a transformation between different crystal forms in the range of 80-120 degrees C. Solid-state 13C NMR, reported in this work for the first time, and Fourier transform infrared (FT-IR) studies of some polymorphs show some differences in intermolecular interactions, especially with carboxylate and hydroxyl groups. Quantum mechanical calculations of the pravastatin molecule are also presented for the first time, obtaining a molecular structure similar to the experimental structure existing within the crystal lattice of the tert-octylamonium salt of pravastatin.     

Physico-chemical characterization of an active pharmaceutical ingredient

The physico-chemical properties and polymorphism of a new active pharmaceutical ingredient entity has been analyzed and the gain of knowledge during the chemical development of the substance is described. Initial crystallization revealed an anhydrous crystal form with good crystallinity and a single, sharp DSC melting peak at 171°C and a straightforward development of this crystal form seemed possible. However, during polymorphism screening, new crystalline forms were detected that were often analyzed as mixtures of crystal forms. The process of characterization and identification of the different crystalline forms and its thermodynamical relationship has been supported by a combination of experimental and computational work including determination of the three-dimensional structures of the crystal forms. The crystal structure of one polymorphic form was solved by single crystal X-ray structure analysis. Unfortunately, Mod B resisted in formation of suitable single crystals, but its structure could be solved by high resolution powder diffraction data analysis using synchrotron radiation. Calculation of the theoretical X-ray powder diffraction pattern from three dimensional crystal coordinates allowed an unambiguous identification of the different crystalline forms. Two polymorphic crystal forms of the API-CG3, named Mod A and Mod B, are enantiotropic whereas Mod B is the most stable polymorph at room temperature up to about 50°C and Mod A at temperatures above 50°C. The mechanism of the solid-solid transition can be explained by analyzing the molecular packing information gained from the single crystal structures. A third crystalline form with the highest melting peak turned out to be not a polymorphic or pseudopolymorphic crystal modification of our API-CG3 but a chemically different substance. This revised version was published online in July 2006 with corrections to the Cover Date.